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Structure of 35231-56-2

Chemical Structure| 35231-56-2

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Product Details of [ 35231-56-2 ]

CAS No. :35231-56-2
Formula : C5H6N2O
M.W : 110.11
SMILES Code : CC1=NC=C(C=N1)O
MDL No. :MFCD09879706
InChI Key :OHFVPBGSKPYIED-UHFFFAOYSA-N
Pubchem ID :535857

Safety of [ 35231-56-2 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 35231-56-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 8
Num. arom. heavy atoms 6
Fraction Csp3 0.2
Num. rotatable bonds 0
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 29.02
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

46.01 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

1.03
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

0.25
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

0.49
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

-0.72
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

0.92
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.39

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-1.24
Solubility 6.41 mg/ml ; 0.0582 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-0.78
Solubility 18.4 mg/ml ; 0.167 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-1.4
Solubility 4.36 mg/ml ; 0.0396 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

Yes
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.79 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

1.27

Application In Synthesis of [ 35231-56-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 35231-56-2 ]

[ 35231-56-2 ] Synthesis Path-Downstream   1~5

  • 1
  • [ 1400809-02-0 ]
  • [ 127199-44-4 ]
  • [ 35231-56-2 ]
  • [ 1400808-34-5 ]
YieldReaction ConditionsOperation in experiment
75% Preparation of D17:The bis-sulfone 2 (11.80 g, 17.23 mmol) was dissolved in NMP (60 mL), followed by adding 2-methylpyrimidin-5-ol 1 (7.59 g, 68.93 mmol). The homogeneous solution was obtained. K2CO3 (9.53 g, 68.93 mmol) was added and the resulting suspension was heated to 100 C for 1 hr, then Boc protected amine (7.32 g, 34.46 mmol) was added and the resulting mixture was heated to 100 C for one more hour, cooled to the room temperature and water (450 mL) was poured into the mixture with stirring. The mixture was cooled to 0 C, filtered and washed the precipitates with water (2×25 mL), dried to give about 12 g of the white solid crude product. The crude solid was dissolved in dichloromethane and silica gel was added. Solvents were removed. Flash chromatography of the residue over silica gel (EtOAc/hexane: 20% to 50% to 90%) to give the pure D17 as a white solid (7.76 g, 75%). LC-MS: M+1: 635.30.
75% General procedure: Example 9 Synthesis of Formula 1 compounds where L=Q and R8 is NHalkyl General Scheme for the bis-sulfone Route: D14 D15 D16 [0518] Tert-buty 2-amino-3-cyano-5-fluoro-lH-indol-7-yl(methyl)carbamate (D13): Crude tert-butyl 3,5-difluoro-2-nitrophenyl(methyl)carbamate (C3) (46.12 g, 0.162 mol) was dissolved in DMF (80 ml) and cooled in an ice-water bath. To it was added malononitrile (1 1.8 g, 179 mmol) followed by the addition of the NaOH solution (12.98 g, 325 mmol) in water (20 ml). After the exothermic reaction mixture was stirred for one hour, the ice-water bath was removed and the reaction was stirred for another one hour. It was then diluted with DMF (80 ml) and water (80 ml), and the atmosphere was displaced with argon. Sodium bicarbonate (109 g, 1.3 mol) followed by sodium hydrosulfite (123 g, 649 mmol) was added. The mixture was well stirred under argon at 40 C for 12 hours (Additional sodium hydrosulfite could be added if the reaction took longer time to complete). After the reaction was cooled down to room temperature, it was diluted with EtOAc (100 ml) and then filtered through a fritted glass funnel. The solids were washed with EtOAc/hexane (1 : 1, 400 ml). The aqueous layer was separated, and the organic layer was extracted with 10% buffer 7 solution (3x 100 ml). The combined aqueous layers were back extracted with EtOAc/hexane (1 : 1, 200ml). The combined organic phases was washed with 5% K2CO3 solution (300 ml). The extractions were then dried over sodium sulfate and concentrated by rotary evaporation to afford the crude compound (D13) as brown color solid (32.6 g, 66 %). LC-MS : M+l : 305.16. [0519] 1H NMR (DMSO, 300 MHz): delta = 10.77 (s, 1H), 6.84-6.80 (m, 1H), 6.69 (s, 2H), 6.69-6.66 (m, 1H), 3.14 (s, 3H), 1.33 (s, 9H). [0520] Tert-buty 2,4-bis(benzylthio)-6-fluoro-9H-pyrimido[4,5-Z>]indol-8- yl(methyl)carbamate (D15): Crude /er/-butyl 2-amino-3-cyano-5-fluoro-lH-indol-7- yl(methyl)carbamate (D13) (4 g, 13.14 mmol), sodium hydroxide (756 mg, 18.9 mmol), and EtOH (40 ml) were added in a 350ml seal tube. The mixture was stirred at 50 C for 15mins to dissolve all NaOH and then cooled down to room temperature. After the atmosphere was displaced with argon, the solution was added with carbon disulfide (10 ml) and dimethyl sulfoxide (1 ml). The reaction was stirred at room temperature for lhour then refluxed at 80 C for 42 hours. It was then cooled down to room temperature and placed in an ice-water bath. Water (20 ml) was added followed by the addition of benzyl chloride (3.33 g, 26.27 mmol). The ice-water bath was removed, and the reaction was stirred at ambient temperature for 5 hours. An additional of benzyl chloride (1.66 g, 13.13 mmol) was added, and the resulting solution was stirred at room temperature overnight. It was diluted with EtOAc (60 ml) and water (100 ml). The resulting solution was partitioned into two layers, and the aqueous phase was removed through an extraction funnel and back extracted with 50 ml of ethyl acetate. The combined organic layers were concentrated by rotary evaporation, and the residue was purified through silica gel column chromatography (15 % EtOAc in hexane) to afford the tile compound (D15) as yellow foam (2.65 g, 36%). LC-MS : M+l : 561.05. [0521] 1H NMR (CDC13, 300 MHz): delta = 8.72 (s, 1H), 7.66-7.62 (dd, J = 8.37, 2.28 Hz, 1H), 7.48-7.27 (m, 10H), 7.05-7.01 (dd, J = 10.14, 2.28 Hz, 1H), 4.69 (s, 2H), 4.55 (s, 2H), 3.37 (s, 3H), 1.48 (s, 9H). [0522] Tert-buty 2,4-bis(benzylsulfonyl)-6-fluoro-9H-pyrimido[4,5-Z>]indol-8- yl(methyl)carbamate (D16): The solution of tert-bu yl 2,4-bis(benzylthio)-6-fluoro-9H- pyrimido[4,5-6]indol-8-yl(methyl)carbamate (D15) (2.28 g, 4.07 mmol) in DCM (50 ml) was cooled in an ice-water bath and added with 3-chloroperoxybenzoic acid 77 % (2.01 g, 8.95 mmol). After the reaction was stirred for 1 hour, the ice-water bath was removed and an additional mCPBA (2.01 g) was added. The resulting solution was stirred at ambient temperature for 7 hours. It was then extract with 5% K2CO3 solution (100 ml), and the aqueous layer was back extracted with DCM (100ml). The combined organic layers were washed first with 5% K2C03 (100 ml) then with 5% NaCl solution (50 ml). It was dried over sodium sulfate and concentrated by rotary evaporation to afford the crude title compound (D16) as bright yellow solid (2.54 g, quantitative yield). LC-MS : M+l : 625.05. [0523] 1H NMR (CDCI3, 300 MHz): delta = 10.07 (s, 1H), 8.49-8.46 (dd, J = 8.64, 2.22 Hz, 1H), 7.54-7.51 (m, 1H), 7.38-7.27 (m, 10H), 4.95 (s, 2H), 4.84 (s, 2H), 3.40 (s, 3H), 1.52 (s, 9H). Scheme: D16 D17 D18 (4.069) [0524] Preparation of D17: The bis-sulfone 2 (1 1.80 g, 17.23 mmol) was dissolved in NMP (60 mL), followed by adding 2-methylpyrimidin-5-ol 1 (7.59 g, 68.93 mmol). The homogeneous solution was obtained. K2CO3 (9.53 g, 68.93 mmol) was added and the resulting suspension was heated to 100 C for 1 hr, then Boc protected amine (7.32 g, 34.46 mmol) was added and ...
  • 2
  • [ 1400809-02-0 ]
  • [ 127199-44-4 ]
  • [ 35231-56-2 ]
  • [ 1400802-17-6 ]
  • 3
  • [ 1400808-67-4 ]
  • [ 127199-44-4 ]
  • [ 35231-56-2 ]
  • [ 1400809-72-4 ]
YieldReaction ConditionsOperation in experiment
0.182 g EXAMPLE 12: Synthesis of Prodrugs at R (5)-2-Amino-A^-(4-((R)-7-amino-5-azaspiro[2.4]heptaii-5-yl)-6-fluoro-2-(2- methylpyrimidiii-5-yloxy)-9H-pyrimido[4.5-Z>]indol-8-yl)-A7-methylpropanamide D16 D77 D78 D79 D80 (4.423) [0576] The mixture of D16 (1.00 g, 1.46 mmol) in trifluoroacetic acid (3.0 mL) was stirred for 30 min at 23 C. Trifluoroacetic acid was evaporated by reduced pressure to provide D77 (quantitative yield) as deep orange solid. This crude material was used for next reaction without further purification. LC/MS (ESI, M+H+) = 585. The mixture of D77 (0.292 g, 0.50 mmol), 2-methylpyrimidin-5-ol (0.165 g, 1.50 mmol) and K2C03 (0.276 g, 2.00 mmol) in NMP (5.0 mL) was stirred for 2 hr at 100 C. After being stirred for 2 hr, the reaction was checked by LC/MS. (R)-tert-bu yl 5-azaspiro[2.4]hepten-7-ylcarbamate (0.318 g, 1.50 mmol) was added at once, the mixture was allowed to stir for 1 hr 30 min at 100 C. The resulting heterogeneous mixture was cooled to 23 C and purified by HPLC to provide D78 (0.182 g, 0.34 mmol) as yellow solid. LC/MS (ESI, M+H+) = 535. To a solution of D78 (0.182 g, 0.34 mmol) and K2C03 (0.094 g, 0.68 mmol) in CH2C12 (10.0 mL) was added (5)-2-(l,3-dioxoisoindolin-2-yl)propanoyl chloride (0.161 g, 0.68 mmol) dissolved in CH2C12 (2.0 mL) at 23 C. The mixture was allowed to stir for 2 hr at 60 C and then cooled to 23 C. The reaction mixture was concentrated by Rotavap and the crude material was purified by HPLC to give D79 as yellow solid. LC/MS (ESI, M+H+) = 736. To a solution of D79 in ethanol (7.0 mL) was added hydrazine (1.5 mL, 30 wt. % solution in water) via syringe at 23 C. The mixture was stirred for 1 hr at 23 C. The reaction mixture was concentrated by Rotavap and the crude material was purified by HPLC to provide 5 as light yellow solid. LC/MS (ESI, M+H+) = 606. The mixture of 5 in trifluoroacetic acid (1.50 mL) was stirred for 30 min at 23 C. The crude material was purified by HPLC to provide a title compound D80 (0.031 g, 0.061 mmol) as white solid. LC/MS (ESI, M+H+) = 506.
  • 4
  • [ 104711-65-1 ]
  • [ 35231-56-2 ]
  • C12H10N4O [ No CAS ]
  • 5
  • [ 109431-87-0 ]
  • [ 35231-56-2 ]
  • C14H21N3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
87% With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 120℃; for 8h; DBAD (CAS: 870-50-8; 1.36 g, 5.90 mmol) was added to a mixture of 2- methylpyrimidin-5-ol (CAS: 35231-56-2; 500 mg, 4.54 mmol), (7?)-(-)-N-boc-3- pyrrolidinol (CAS: 109431-87-0; 1.11 g, 5.90 mmol) and triphenylphosphine (1.55 g, 5.90 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 18 h and concentrated to dryness. The residue was purified by flash column chromatography (silica, EtOAc in heptane, gradient from 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo to yield intermediate 32 (1.1 g, 87%) as a colorless oil.
 

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Technical Information

Categories

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